Researchers are closing in on potential therapies for dementia

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A 2006 survey by the MetLife Foundation reveals that U.S. adults fear Alzheimer's and its accompanying memory loss more than heart disease, stroke, or diabetes. Among adults over 55, Alzheimer's tops the list of most dreaded diseases.

The words on the pink post-it note, thumbtacked to a wall in his home, can't be any clearer: "This house, in Oak Park, Illinois, is where Bob and Donna live." But Bob Berry shakes his head. No. I live in Wichita Falls... don't I? Why, I have an exam tomorrow at my high school.

I've talked to my father about it... or have I? Bob wonders. Lately, he can't be sure of anything. Except the nice woman. The one who always seems to be around, the one with the kind face who now takes his hand. Something about her seems familiar. But what?

She hates having to tell him — again — but what can she do? Ever since a near-fatal cardiac arrest robbed Bob's brain of precious oxygen for close to 5 minutes, his memory has been like a blackboard swiped clean every few moments — erased. Pieces of information — the time, what day it is, where he lives — dissolve like vapor trails.

So he has to be reminded that he is not a high-school student in Wichita but a 63-year-old man who is an accomplished brain scientist; that he can't see his father because his father died long ago. And he has to be told that Donna is not his mother, as he has guessed on occasion, but the person he has lived with for 15 years, the woman who rescued him when he nearly died, the woman he loves.

In short, Bob has to be treated like a person in the early stages of the very ailment he devoted his life's work to curing — Alzheimer's disease.

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The one consolation is that, unlike the Alzheimer's victims he once studied, Bob will not worsen. He will be spared the agonizing descent into full-blown dementia. But he will never be the same. He will never do the work of a brain scientist, never again author a seminal study, never be able to tap his most powerful resource, the one that might help him help himself: his mind.

That's the conventional thinking, at least. A bolder view, one rooted in a groundswell of intriguing advances in memory research, suggests a different notion: Never say never.

The mystery of memory
Memory has been a source of wonder as far back as recollection itself. The early Egyptians mused on it. The Greeks named a goddess, Mnemosyne, after it. The Roman orator Cicero astonished citizens with his mastery of it. In the centuries that followed, shrinks, scientists, and dreamers have pursued, poeticized, and puzzled over it.

However, until scientists benefited from a succession of breakthroughs in brain mapping — CAT scans and MRIs initially, and diffusion tensor imaging, positron emission tomography (PET) scans, and functional MRI more recently — our understanding of exactly what memory is and how it works was more art than science, the product of guesswork and hunches.

Even now, a definitive explanation of the process eludes us, although here's what researchers believe is happening: First, you experience something. That experience, in turn, converts into a pulse of energy that zips along a network of neurons and lands for a split second in your sensory memory, which is a way station for your immediate impressions. From there, the information — a phone number, say, that you're about to dial — is shunted into short-term memory where it's available for anywhere from a few seconds to a couple of minutes.

After that, a seahorse-shaped brain structure called the amygdala decides if the experience (the number you dialed) should be discarded as nonessential or shuffled along to long-term storage. For the latter option, the brain locks in information based on such factors as the importance of the moment (a first kiss, a childhood trip to the beach, the smell of mom's cooking), the emotion attached to the event (a loved one's death, the joy of a child's birth), or the importance you assign to the information (a Social Security number).

This long-term storage is further broken down into two categories: declarative memory (the recollection of specific events or episodes) and nondeclarative "muscle memory" (skills like riding a bike or driving a stick shift). Many scientists also identify semantic memories, which are factual and unrelated to specific experiences. For example, semantic memory tells you what an omelet is, but not whether you ate an omelet for breakfast that morning.

Explaining just how you retrieve the information — how you pull a name and a face out of the 100 billion or so neurons forged into the trillion-plus possible patterns — is trickier. The best and latest science strongly suggests that your brain activates the same pattern of neurons that was used to store the information. In other words, memory is like an electronic map route that lights up when you want to remember something.

At least that's the nuts-and-bolts explanation. For brain scientists striving to unlock the mystery of memory, the process is much more profound, something spoken about in almost reverential tones — a quest as fundamental and soul-stirring as science has to offer. "Understanding memory is easily the equal of exploring the galaxies," says Howard Eichenbaum, Ph.D., the director of Boston University's center for memory and brain. "It's like figuring out the universe of who we are."

Memory damage
On a muggy Chicago night in 2006, Bob and Donna had just settled down to dinner when Bob, poised over a forkful of green beans, gasped, "Oh, my god," and collapsed face-first into his plate.

Assuming he had suffered a heart attack, Donna raced to call 911. Help arrived quickly, mere minutes after Bob's collapse. Paramedics were able to revive him, but he then slipped into a coma. For weeks, Donna and Bob's family, including his two sons, Robb and Kevin, waited to find out the degree of brain damage he had suffered.

As an Alzheimer's researcher, Bob had witnessed firsthand the devastation of memory loss. And he had made his wishes clear, should he ever find himself in such a predicament.

"He said, 'If I have a chance of regaining brain function, keep me plugged in,'" Donna recalls. "But if I can't use my brain, then don't."

When Bob finally woke up, family members were thrilled to learn that his mind was largely intact. But they also realized that a part of him had been lost. He seemed to recognize Robb and Kevin, but he looked puzzled when he saw Donna. Just how bad his memory had been damaged wasn't immediately clear to anyone, including the doctors. So Robb developed his own primitive exam.

"Hey dad, know any pirate jokes?" he'd ask. Bob would shake his head no. "Pirate walks into a bar with a steering wheel sticking out of his fly. Bartender says, 'Hey buddy, what's with the steering wheel sticking out of your pants?' The pirate says, 'Yar, it's drivin' me nuts!'"

Bob would laugh. Every time. He had no idea that Robb had been telling him the joke nearly every day for weeks. Or that a part of his son cried every time his father laughed.

Fear of dementia
Memory is hot.

We are obsessed with it, from movies ("Memento," "50 First Dates," "The Bourne Identity," "Eternal Sunshine of the Spotless Mind") to best-selling books to unproven memory aids like ginkgo biloba, one of the most popular supplements in the United States, with $109 million in sales in 2005.

In fact, the Web hums with "brain-boosting" products, such as Focus Factor, Memory Formula, and Alert! Nintendo has sold over 17 million copies worldwide of its Brain Age and Brain Age 2 games, including 5 million in 2007. Nintendo also offers enrollment in "Big Brain Academy" for the Wii, a virtual college with memory games and quizzes.

The fascination extends beyond pop culture. The best, brightest, and most ambitious scientists and students, perhaps sensing the potential for Nobel prizes and pharmaceutical riches, have made memory research the "it" field of brain study. "Just this month alone, there are three new textbooks on the neurobiology of learning and memory," says James McGaugh, M.D., a neuroscientist at the University of California at Irvine. "Ten years ago, there wasn't a single one."

What happened? Why are we suddenly so aware of this obscure corner of brain research, once the realm of lobotomies and weird experiments with cadavers and electrodes, and why are researchers so impassioned about pursuing it?

One answer is fear. "People are worried," says Barry Gordon, M.D., Ph.D., founder of the memory clinic at Johns Hopkins University. "If you look back to the 1930s, young men were dying in their 20s of tuberculosis. Nobody was worrying about Alzheimer's or senility." Then came the nightmarish notion of early onset Alzheimer's. Suddenly the dread of permanent forgetfulness gripped the young as well as the old. Doctors were bombarded with calls from patients terrified by tip-of-the-tongue moments and misplaced car keys.

Never mind that developing early onset Alzheimer's is as likely as being struck by lightning, or that absentmindedness often has more to do with stress and overtaxed minds than physical disease. The fear of Alzheimer's became almost phobic. "Dementia paranoia" was born.

A 2006 survey by the MetLife Foundation bears out the public's obsession: U.S. adults now fear Alzheimer's and its accompanying memory loss more than heart disease, stroke, or diabetes. Among adults over 55, Alzheimer's tops the list of most dreaded diseases.

The kicker is that the people who worry most about their memories are actually less likely to have trouble. "If you really had a serious memory problem, then you would not remember what you forget," says Dr. Gordon. So the fact that you recognized that you forgot an appointment indicates that your memory is probably functioning just fine. The lapse is probably due to other factors — too much on your plate, for example, or distractions. The true test is not whether you are worried. "If your spouse or friends do not notice anything wrong with your memory, then you can relax," Dr. Gordon says.

But fear isn't the only factor driving our memory obsession. More and more, we see good cognitive function as a career necessity.

"The world is demanding that we think better," notes Dr. Gordon in his book Intelligent Memory. "There's an intellectual race going on, especially in the workplace."

The result, adds Dr. McGaugh, is that "you have a new generation of people who are focusing on memory as an asset, in addition to money, houses, and cars."

The desire to increase the value of that asset accounts for the proliferation of memory-enhancing products. "Why are supplements like ginkgo biloba and computer programs like Brain Booster selling?" Dr. McGaugh asks. "Because people want an edge on memory."

Finally, experts say, people recognize more than ever the crucial role memory plays in health and happiness. "All we do as humans is based on memories," says Esther M. Sternberg, M.D., the author of "The Balance Within: The Science Connecting Health and Emotions." "You create your sense of self from accretions of many different memories. Memories of what you've done, of your emotional reactions to those experiences, and of the settings where they took place are all intimately connected to feelings of well-being and happiness."

For confirmation, says Dr. McGaugh, "all you have to do is look at people who have lost their memories and you can see they're no longer themselves. All that we do as humans is based on memory. Without it, we're nothing. Memory is hot because people have come to understand that it is our most important human capacity."

Unable to remember
Before his memory became as fragile and impermanent as a snowflake, Bob and his colleague Lester "Skip" Binder, Ph.D., used to refer to their work by joking, "If I remember correctly, I study Alzheimer's disease." It was funny then. Now it's a sad reminder of what Bob lost on July 29, 2006.

"You have to understand that Bob was a very bright man and a very high-functioning person," says Binder, who continues to run the neuroscience lab that he and Bob built into a cutting-edge center for Alzheimer's research. "He had a razor-sharp wit — really quick. Now he has trouble remembering whether he shaved in the morning. He can't take a walk because he'll forget where he is." Once upon a time, the pair would bat around their latest theories on brain function over a lunch martini. Now, says Binder wistfully, "he has the same core personality but he's not really Bob anymore."

The technical name of Bob's condition is anterograde amnesia, or the inability to form new memories as a result of damage to the hippocampus. So he knows what breakfast is, but he can't tell you what he ate on a given morning. He can be told that his parents are dead, and ask 5 minutes later if he can talk to his father. Bob also suffers somewhat from retrograde amnesia, meaning he has holes in his past. He knows that he worked in some capacity at Northwestern, for example, but he can't remember any of his research or that of his colleagues. Frankly, Bob's cognitive therapist at Northwestern, Linda Laatsch, Ph.D., is amazed by the inconsistencies in his memory. Sometimes he says he's living in Texas, sometimes he correctly recalls that he now lives in Oak Park and that he had a heart attack. Amnesia is not all or nothing.

The brainI visit Bob at his home just outside Chicago. He's wearing jeans and a sweater vest, and as he sits there working on a crossword puzzle by the fire with his reading glasses low on his nose, he looks every bit the college professor and scientist. He reminds me a little of Hal Holbrook in "Our Town," in fact, poised to pass along some Grover's Corners gossip.

He looks up when Donna introduces me. "Bob, do you remember I told you about Bryan?" she asks. He glances at me, and then back at her. "Not really, no," he says, with an apologetic smile. She warned me that he wouldn't know who I was — and that even after she introduced me, he would forget, within a couple of minutes, why I was there. As she shows me through the home, I realize she wasn't exaggerating the extent of Bob's condition.

On almost every wall, pink and yellow Post-it notes curl out, symbols of Bob's fleeting memory. "This is Bob's room," reads one, underlined by a hand-scrawled arrow. This is Oak Park," says another. A bathroom note spells out his morning routine: "Shower, Shave, Deodorant, Dress." A fact sheet describes Bob's life in kindergarten prose: "Bob lives in Oak Park. Bob is 62 years old. Bob had a cardiac arrest on July 26, 2006. Bob has amnesia because of that."

As she reaches the kitchen, Donna pauses for a moment. She wants me to know how deeply grateful she is that Bob survived, and how lucky she and Bob both feel that he at least has some memories intact. "Most people just die on the spot," she says.

Still, she admits that life with an amnesia victim can be trying: having to constantly monitor Bob to make sure he doesn't wander from home and get lost; needing to remind him again and again to dress so that he can make his therapy appointment on time; being mistaken by him for someone else after she's lived with him for so many years.

Stopping in front of the refrigerator, she shows me her last line of defense when life becomes too tough. It's a bit of dark humor she knows Bob would have appreciated once upon a time. "Phillip's Milk of Amnesia," the fridge magnet reads. "For people who can't remember shit."

Causes of memory loss
Until very recently, researchers believed that aging and memory loss went hand in hand. And assuredly, our memories do slip somewhat as we grow older.

"Our brains, like our muscles, do slow with age," says Dr. Gordon. "In addition, there may actually be decreased efficiency of the circuits that lead to permanent memory."

But some of the latest and most intriguing memory research suggests that memory loss has far less to do with chronological age than with physiological problems that strike people, whether they're in their 30s or their 60s.

"There has long been an assumption that age-associated memory decline existed and that Alzheimer's was just a dramatic example," says Catherine Myers, Ph.D., co-director of the Rutgers memory disorders project. "We're now coming to the conclusion, however, that the brain really should not deteriorate much with age and that, if it does, its deterioration is likely the result of pathology."

Poor blood circulation is the second most common cause of dementia, after Alzheimer's. The implication, says Myers, is that "if physical factors are to blame, then there's hope of fixing the problem."

She cites a 2006 University of Illinois study review, which concluded that physical activity improves brain function in people in virtually every way, including memory. And researchers in the Netherlands reported that simply walking for an hour twice a week can boost a person's power of recall.

Memory thievesAnother factor in memory deterioration may be a drop in social activity among the elderly. A study by the Harvard school of public health published in July reports that older people with the highest level of social integration had the slowest rate of memory decline over a 6-year period. The exact reason remains unclear, but experts suspect that the mental workout inherent in social interactions plays a role.

There are yet other memory thieves, including sleep deprivation. Think about it: "If you're chronically overtired, attention and concentration will be low, and it will be hard to introduce new information into your brain," says Myers. A lack of sleep may also prevent your brain from doing "memory housekeeping" essential to recalling information learned the previous day, she says.

Depression is another culprit. One study, by Rush University medical center, in Chicago, determined that people who are often stressed or depressed are 40 percent more likely to develop memory problems than people with more positive dispositions. This may be because depressed people are less motivated and therefore less attentive to new information. Then, too, depression saturates our bodies with high levels of stress hormones, such as cortisol. In small doses, that's fine — cortisol can actually give memory a jolt (a clue to why we remember traumatic life events so vividly). But too much can damage regions of the brain crucial to memory.

Among men specifically, one of the most intriguing explanations is also one of the most hotly debated. Despite a 2005 study linking low testosterone levels to memory loss, more recent research, including a 2007 University of Illinois at Chicago study, blames high levels of the hormone. At first glance, the discrepancy may seem discouraging. But hormones are tricky. "In general it's safe to say that all our hormones, including those affecting the brain, have a carefully tuned operating range, and that either too much or too little can knock the system out of kilter," says Myers. "So it's entirely possible that both findings are correct — that either too much or too little of the hormone can interfere with normal brain function."

The bigger point, adds Myers, is that researchers are making headway. "We have new ways to look at the brain that we've never had before, and we have an understanding of the genetics. This may be the most exciting time for memory research."

Potential therapies
Virtually every day for 6 months, in a scene right out of "Groundhog Day," Bob would introduce himself to his former colleague, Linda Laatsch, Ph.D. She would put him through a battery of tests and memory exercises and bid him goodbye, and he'd introduce himself again the next morning.

The brainUntil recently, little could be done for people like Bob who suffered damage to the hippocampus. Even now the options are limited. But as Bob struggles to remember information as basic as the identities of his doctor and former colleagues, researchers are closing in on potential therapies.

At Boston University, for example, a team led by Eichenbaum is studying the activity of neurons in the hippocampus. "If we can unravel the memory code in the nerve-cell networks, then we can focus our research on how drugs affect memory storage and retrieval. This will put us a major step ahead of the current approach, right into the circuitry on which drugs exert their effects."

Other research groups are on a similar mission, each racing to discover what makes the hippocampus tick. It's not surprising that scientists are drawn to the structure. Because of its crucial role in forming new memories, you would be doomed to a life lived in 2-minute increments without it.

"The hippocampus is responsible for updating moment-to-moment reality," says Sandra Weintraub, M.D., a clinical neuropsychologist at Northwestern University Feinberg School of Medicine and the doctor who first evaluated Bob. "As things are streaming by you, it takes it all in and then stores it in different parts of the brain so that later on you can go back and retrace your steps and think, 'Gee, what did I do yesterday?'"

While most research is focused on drug development, one scientist is pursuing a far more audacious approach. Theodore Berger, Ph.D., the director of the center for neural engineering at the University of Southern California, is trying to create a prosthetic hippocampus. The device, a microchip currently being tested in rats, would perform the same railroad-switch function as the hippocampus does, accepting thoughts on one end and then shunting them into long-term memory on the other.

The implications are astounding. Bob could relearn his entire history and it would stick. Donna would always be Donna and Oak Park would always be home.

"Berger's work is bold and imaginative," says Dr. McGaugh. "It does seem to be a long shot, but so is much — even most — translational research. If his approach works, it would be a terrific achievement."

Still, skepticism abounds. At best, critics say, such a device is years if not decades away. At worst, they say, it can't be made.

Berger, naturally, is more optimistic. Already he has successfully bypassed various slices of rat hippocampus. The next step, currently under way, is to implant a chip into a live rat. "Most people think we're crazy," Berger says. "But we are more convinced than ever that it's feasible."

When I tell Donna about Berger's research, she immediately looks it up on the Internet. "Whenever this is ready for humans, even just for trials, I would definitely consider having Bob do it," she says, "even though it sounds pretty scary putting stuff in people's heads. I think the possible benefits outweigh the risks, and I'm sure that Bob would agree."

In the meantime, she is learning to cope. On some things, she's unyielding — she never lets Bob slide on her identity, for instance. But if at all possible, she tries not to challenge him when he asks where his father is. Like a loved one dealing with an Alzheimer's patient, she tries to distract him or change the subject. Some memories are best left alone.

Skip Binder sometimes brings by some of Bob's old lab partners. They order pizza and talk over Alzheimer's research just like old times. Bob doesn't participate much, Binder says. But no matter; his presence is enough.

Robb is content to watch the Cubs with his dad, even though he knows that by the third inning Bob will have forgotten what happened in the first. "I'm just glad I can be with him," Robb says.

Once in a while, though, if Robb remembers, he'll ask his father a question, one he knows will stump the old man but also bring a smile, if not of recognition, then of some glimmer of lost memory vaguely recalled: "Hey dad, know any pirate jokes?"